There are more than 500 distinct kinase enzymes coded in the human genome. Protein kinases are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. Protein kinases are believed to perform a central role in signal transduction pathways regulating a number of cellular functions, such as cell cycle, cell growth, cell differentiation, cell death (apoptosis), and tissue/organ organization. Aberrant or excessive activity or dysregulation of activity of protein kinases has been observed in many disease states, including benign and malignant proliferative disorders as well as inflammatory disorders and immune system disorders. Protein kinases are, therefore, attractive therapeutic targets for disease treatment.
For instance, dysregulated activity of the receptor tyrosine kinase of the platelet growth factor receptor (PDGFR) family has been implicated in various proliferative disorders. Gene amplification or upregulation of PDGFR occurs in patients with gliomas or sarcomas. Constitutive activation of PDGFRα has been found in patients with chronic myelomonocytic leukemia (CML). Gain of function mutations and small deletions in the PDGFRα gene has also been found in patients with gastrointestinal tumors (GIST) and in patients with idiopathic hypereosinophilic syndrome. PDGFRβ has been found to be expressed in the tumor stroma in a majority of solid tumors, which makes this receptor a potential target for anti-tumor therapy. PDGFRβ has also been found to be expressed in tumor vasculature, and studies have suggested PDGFR-β inhibition as one mechanism for anti-angiogenic therapy.
A second member of the PDGFR family, FLT3 (also called Flk2), plays an important role in the proliferation and differentiation of hematopoietic stern cells, and activating mutation or overexpression of this receptor is found in AML. More than a dozen known FLT3 inhibitors are being developed, some of which have shown promising clinical effects against AML. The FLT3 receptor is also expressed in a large portion of dendritic cell progenitors and stimulation of the receptor causes the proliferation and differentiation of these progenitors into dendritic cells (DC). Since dendritic cells are the main initiators of the T-cell mediated immune response, including autoreactive immune response, inhibition of FLT3 is a mechanism for down-regulating DC-mediated inflammatory and autoimmune responses. One study shows the FLT3 inhibitor CEP-701 to be effective in reducing myelin loss in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. A high level of the FLT3 ligand is found in the serum of patients with Langerhans cell histiocytosis and systemic lupus erythematosus, which further implicates FLT3 signaling in the dysregulation of dendritic cell progenitors in those autoimmune diseases.
Kit (or stem cell factor receptor, or SCFR) is another member of the PDGFR family, and the presence of kit mutations is a key diagnostic marker for gastrointestinal stromal tumors (GIST). Gleevec (imatinib mesylate or STI571), the first FDA-approved receptor tyrosine kinase (RTK) inhibitor originally approved for c-Abl-mediated chronic myeloid leukemia, gained FDA-approval for Kit-mediated GIST in 2002 and has validated the molecular-based approach of Kit inhibition for the treatment of GIST. Gain of function mutations is also associated with mast cell/myeloid leukemia and seminomas/dysgerminomas. Kit mutations have been also identified in certain melanomas and recognized as a potential therapeutic target for melanoma.
Therefore, pharmacological modulation of one or more kinases would be useful in slowing or stopping diseases such as cancer that are induced by inappropriate proliferation of cells. Currently, many protein kinase inhibitors have been developed and are used widely for clinical applications.
Related patents, including WO 99/55335, WO 00/27822, WO 00/59901, U.S. Pat. No. 6,297,238 B1, U.S. Pat. No. 6,245,796 B1, WO 01/87846 A2, U.S. Pat. No. 6,462,036 B1, WO 2004/080973 A1, U.S. Pat. No. 7,485,730, EP 1602658 A1, US 2007/173488 A1, and U.S. Pat. No. 7,468,371 B2, are incorporated herein for reference.
A need still exists in the art for protein kinase inhibitors, particularly in class III receptor tyrosine kinase (RTK) family such as FLT3 kinase, c-KIT kinase, and PDGFR kinase, which have efficacy in the treatment, prevention, or amelioration of RTK-related diseases.